Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons and concomitant muscle wasting. This results in increased paralysis and death within 2-5 years after diagnosis (Wijesekera and Leigh, 2009). The cause of death of motor neurons is unclear, but abnormal mitochondria, ubiquinated inclusions and neurofilament aggregates are thought to contribute.
Mitochondria are responsible for beta-oxidation of fatty acids and oxidative phosphorylation by the tricarboxylic acid (TCA) cycle and the electron transport chain, producing most of the adenosine triphosphate (ATP), the primary cellular energy source that is necessary for cell function and survival. Thus, impaired mitochondrial function in motor neurons and muscles would result in defective energy metabolism and a reduced capacity to produce ATP.
Triheptanoin, the triglyceride of heptanoate (C7 fatty acid), is a novel metabolic therapeutic that is being used in the USA to treat patients with rare genetic metabolic disorders of fatty acid oxidation (Brunengraber and Roe, 2006, Roe and Mochel, 2006). Triheptanoin provides the body with heptanoate, which as a medium chain fatty acid diffuses into the mitochondria to be metabolized to propionyl-CoA by beta-oxidation. Alternatively heptanoate is metabolized in the liver to the C5 ketones, β-hydropentanoate and β-ketopentanoate, both of which are taken up by cells by monocarboxylate transporters. Carboxylation of propionyl-CoA produces methyl-malonyl-CoA, which can be metabolized to succinyl-CoA, resulting in anaplerosis—the refilling of deficient C4 (containing four carbons) intermediates of the TCA cycle (FIG. 1). Anaplerotic enzymes include pyruvate carboxylase (Pcx) producing oxaloacetate in neurons and muscle, and most importantly in muscle glutamic pyruvic transaminases 1 and 2 (Gpt1 and 2), which catalyze the reaction pyruvate+glutamate<=>α-ketoglutarate+alanine and propionyl-CoA carboxylase subunit A (Pcca) and B (Pccb) and methylmalonyl-CoA mutase (Miut, FIG. 1).
Superoxide dismutase 1 (SOD1) protein mutations have been found in approximately 20% of patients with familial ALS and in a subset of patients with sporadic ALS. While usually found in the cytosol, mutant SOD1 accumulates within mitochondria and appears to contribute to many of the mitochondrial perturbations found in ALS (Turner and Talbot, 2008, Vucic and Kieman, 2009, Shi et al., 2010, Milani et al., 2011, Cozzolino and Carri, 2012). Mice overexpressing mutations in SOD1 are currently one of the best animal models for ALS.